Pediatric FA affects 6-8% of children, in whom it is the major risk factor for anaphylaxis and eosinophilic esophagitis (EoE). The pathogenetic mechanisms leading up to food sensitization and target organ inflammation are poorly understood. A better understanding of FA pathogenesis will be essential to the development of specific diagnostic and therapeutic tools to combat these widespread diseases. The proposed work represents an entirely new line of inquiry into FA pathogenesis. Building on novel preliminary (included in a manuscript favorably reviewed by JACI) which demonstrate that invariant Natural Killer T cells (iNKTs) are 1) stimulated by milk derived lipids to secrete Th2-specific cytokines, and 3) are qualitatively and quantitatively different in children with FA (IgE mediated milk allergy or active EoE) than in their healthy or in remission counterparts, the proposed work will define the role of iNKTs in FA development and expand our understanding of how milk-SL (milk-sphingolipids) specifically activate iNKTs to induce FA. Specifically, I hypothesize that: 1) iNKTs are sequestered at the site of the allergic inflammation in FA children;2) iNKTs stimulated by food-SL promote chronic inflammation via macrophage activation 3) Milk-SL activate iNKTs in a CD1d-restricted fashion using specific TCR rearrangements. To test these hypotheses, I will study iNKTs in children with EoE, for whom I have access to both PB and esophageal biopsy samples. In tandem, I will perform mechanistic studies using adult iNKTs, which afford the large number of cells necessary for such studies. Given the novel results reported in my preliminary data, I believe that the proposed research will revolutionize our understanding of food's influence on the immune system, and provide a new paradigm for food sensitization in which the lipid content of food, not just its protein content, influences the balance between oral tolerance and sensitization. My scientific and clinical training thus far has uniquely positioned me to address the above questions. My present clinical practice in the busy Center for Pediatric Eosinophilic Disorders at The Children's Hospital of Philadelphia, along with its 80% protected research time of my academic appointment, afford me the opportunity to focus my research efforts on a novel line of inquiry in food allergy. Today, my laboratory strives to understand how food-derived lipids contribute to food allergy sensitization, and I have developed state-of- the-art techniques to investigate, at a molecular level, iNKTs in humans. I am supported in my research by great mentors leaders in the fields of iNKT, and T cell biology (Dr Koretzki and Dr Nichols) and of clinical allergy (Dr Spergel). I also sought support from leader in the field of iNKT and NK biology (Dr Brenner and Dr Orange). CHOP and the University of Pennsylvania School of Medicine provide an ideal environment in which to integrate my previous clinical and laboratory experiences to become an independent physician scientist Our proposal, "Role Invariant NKT cells (iNKTs) in eosinophilic esophagitis" is aimed at understanding if iNKTs play a role in eosinophilic esophagitis, using it as a model of food allergy. We believe that the answer is that iNKTs stimulated by food derived lipid can create a Th2 skewed environment necessary for food allergy sensitization. Our work will test this hypothesis and be of broad relevance in that it will define a novel mechanism by which immunological function can be regulated by dietary lipids as well as more specific insight into iNKTs function and iNKTs role in food allergy.